Toxoplasmosis in pregnancy (toxo, congenital toxoplasmosis)

1. What every clinician should know

Congenital toxoplasmosis is not common in the United States. It is caused by the intracellular parasite Toxoplasma gondii and is estimated that there are between 500-5,000 cases annually. However, because it is not a reportable disease in the United States, these estimates are difficult to confirm. This is in contrast to the worldwide burden of congenital toxoplasmosis, which is much higher in many parts of the world, such as western Europe.Congenital infection is generally thought to occur following primary maternal infection. In the United States, maternal seroprevalence is estimated to be approximately 15%. Acquisition occurs by ingestion of infectious oocysts.

Maternal infections are usually asymptomatic. Fetal infection tends to occur less frequently early in pregnancy but is more likely to be severe. Maternal infection in late gestation is associated with a very high risk of fetal infection, but these infections tend to be less severe. Overall, approximately 85% of congenital infections are subclinical at birth. However, symptomatic fetal infection can cause severe fetal abnormalities, such as chorioretinitis, hydrocephalus, and cerebral calcifications, and can even result in stillbirth or neonatal death.

Risk factors for maternal acquisition of toxoplasmosis include those leading to exposure to infectious oocysts. The cat is the only natural host of the obligate intracellular parasite, division occurs in the cat intestine. Human transmission occurs by ingestion of oocystscontaining sporozoites from exposure to infected cats, foods contaminated by cat feces, or ingestion of bradyzoites in the meat of animals that have acquired the infection via ingestion of cat feces.

Pregnant women can be exposed by contact with infected cats, usually cats that go outdoors, particularly if they change the litter boxes of these animals. They can also acquire toxoplasmosis if they ingest poorly washed produce from contaminated soil, or ingest raw or undercooked meats from infected farm animals. In fact, a study in Belgium found a reduction in matenral toxoplasmosis as a result of education focusing on avoiding eating raw or undercooked meat, use of gloves for handling soil, and abstaining from changing litter boxes unless a cat is strictly an indoor cat.

2. Diagnosis and differential diagnosis

There are two generally accepted reasons to evaluate a patient for toxoplasmosis. The first is a suspicion of a maternal infection. Fetal diagnosis then should follow when there is serologic evidence of maternal infection. The second is in the setting of an abnormal fetal ultrasound with findings suspicious for congenital toxoplasmosis infection.

The American College of Obstetrics and Gynecology (ACOG) recommends against routine screening for toxoplasmosis in pregnancy, except in the setting of maternal HIV infection. This is due to the relatively low prevalence of disease in the United States in conjunction with the high false positive rate of serologic screening.

Routine screening in the U.S. would lead to innumerable unecessary interventions for very few true positive cases. For this reason, ACOG recommends testing only for those in whom a high risk of acute infection is suspected. This might include the unusual circumstance in which a pregnant woman has been changing the cat litter or having close contact with a cat that is new to the household and also spends time outdoors. Maternal HIV infection is another accepted reason for testing.

Ultrasonographic findings suspicious for fetal toxoplasmosis infection include ventriculomegaly, intracranial calcifications, microcephaly, ascites, and growth restriction. These findings may also be seen in other conditions, however, and these should also be included in a differential diagnosis. Conditions that can cause similar ultrasound findings and occur more commonly than congenital toxoplasmosis include various aneuploidies. Other common infectious etiologic agents include Cytomegalovirus or Parvovirus B19.

When maternal infection is suspected, serologic screening should be conducted by a reference laboratory. Testing for toxoplasma specific antibodies are conducted for detection of IgM and IgG. Because of the false positive rates, ruling out recent infection is much more reliable than testing to rule in acute infection. A negative IgM test is reliable to exclude a recent infection. However, a positive IgM test can be either a false positive or can persist following a prior infection for months to years. In the setting of a positive IgM and IgG, IgG avidity testing can be conducted. Again, a high avidity test is suggestive of past infection, and in the early part of pregnancy essentially rules out recent infection. However, a low avidity can persist for months and thus cannot definitively diagnose recent infection but can propmpt further evaluation. This further evaluation may take the form of serial serology for maternal infection or of fetal testing, via amniocentesis. Serial serology can be helpful to either identify IgG seroconversion or demonstrate in an increase in IgG titer in someone with a recent illness.

The most common way to diagnose fetal infection is by amniocentesis. In the past, fetal blood sampling was used, but this method was associated with increased fetal risk and is not a superior diagnostic approach. Amniocentesis is conducted under ultrasound guidance and amniotic fluid can be evaluated for the presence of T gondii. Polymerase chain reaction (PCR) testing should be performed but results should be interpreted with caution since both false positive and negative results have been reported.

Neonates suspected of having infection can also be tested by PCR techniques from blood or body fluids. Isolation of parasites is technically difficult, and require live parasites for culture. Detection of tachyzoites in tissue or body fluid smears indicates active pathology.

3. Management

Antepartum

There are two major approaches to management of mothers with suspected toxoplasmosis. One is to prevent transmission of toxoplasmosis to the fetus. The second is to treat infected fetuses. The gestational age and level of concern for active fetal infection will dictate which of these goals should be the focus of the provider at any one time.

After documentation of maternal infection, therapy should be begun with Spiramycin. Spiramycin may decrease the risk of fetal infection. It concentrates in the placenta and is thought to prevent transmission there. However, because it does not cross the placenta and reach the fetus well, it is not reliaible for therapy of an infected fetus.

Spiramycin is not commercially available in the United States, and an application must be filed with the Food and Drug Administration (FDA) to obtain it for us in appropriate clinical situations. The FDA has a program available to clinicians, with guidance on their website (www.fda.gov), entitled "Physician request for an individual patient IND under expanded access for non-emergency or emergency use". This webiste provides access to a form for the request as well as facsimile and telephone numbers for contact by drug category, in this case, anti-infectives.

Spiramycin is used for prophylaxis against fetal infection early in pregnancy and can continue throughout the pregnancy if there is no evidence of fetal infection. The usual dose for prophylaxis against congenital toxoplasmosis is 1gram three times daily.

Once a pregnant woman has reached approximately 18 weeks gestation, and at least four weeks have elapsed from the time of presumed maternal infection, assessment of fetal infection should be considered. Detailed ultrasonography should be performed to assess for findings typical of congenital toxoplasmosis. Amniocentesis should be not be pursued earlier to test for active infection in the amniotic cavity in order to minimize the risk of false negative results. Polymerase chain reaction (PCR) testing for T. gondii can be conducted after this time with 80-90% sensitivity and over 90% specificity in appropriately selected patients.

If the amniocentesis is positive for the presence of T. gondii, fetal therapy should be pursued. Therapy is similar to that provided to infants and has been shown to decrease the severity of the infection. The regimen consists of a combination of pyrimethamine and sulfadiazine. Folinic acid is given as well to prevent bone marrow suppression. Therapy is continued throughout pregnancy until delivery. After birth, the infant is tested and therapy decisions are made based upon the clinical scenario, but generally is continued for the first year of life.

4. Complications

Complications of maternal and subsequent fetal infection include miscarriage, stillbirth, and long-term neurologic impairment. Infected infants can experience hepatosplenomegaly, chorioretinitis, deafness, and hydrocephalus. Complications of infections are more likely to occur when fetal infection occurs early in pregnancy, although fetal infection is more likely to occur at later gestational ages.

5. Prognosis and outcome

Long-term consequences for infected children include ocular lesions, which despite therapy, can develop well into adolescence. A significant proportion of infected children experience some ocular lesions, which often impact vision. Childhood hydrocephalus is also reported. In people who survive into adulthood with congenital toxoplasmosis, quality of life scores are similar to those of the general population. Maternal prognosis is good, with few, if any, complications in the absence of immunocompromise.

6. What is the evidence for specific management and treatment recommendations

"ACOG practice bulletin. Perinatal viral and parasitic infections. Number 20, September 2000. (Replaces educational bulletin number 177, February 1993). American College of Obstetrics and Gynecologists". International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.
vol. 76. 2002. pp. 95-107.

http://www.cdc.gov/dpdx/toxoplasmosis/dx.html.

Ajzenberg, D. "High burden of congenital toxoplasmosis in the United States: the strain hypothesis?". Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.
vol. 54. 2012. pp. 1606-7.